Systemic mastocytosis (SM) is a rare myeloproliferative neoplasm characterized by the accumulation of neoplastic mast cells in one or more extracutaneous organs. The 2008 World Health Organization (WHO) classification recognizes 7 variants and 1 subvariant of systemic mastocytosis patients. These include cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD), mast cell leukemia (MCL), mast cell sarcoma, and extracutaneous mastocytoma, plus a subvariant of ISM termed smoldering systemic mastocytosis (SSM). The major diagnostic criterion in systemic mastocytosis is the presence of multifocal clusters of morphologically abnormal mast cells in the bone marrow in association. Minor diagnostic criteria include elevated serum tryptase level, abnormal mast cell expression of CD25 and/or CD2, and presence of KITD816V mutation. Advanced systemic mastocytosis is characterized by organ damage due to infiltration of mast cells. See Valent et al., Eur. J. Clin Invest., 2007, 37:435-453 and Valent et al., Allergy, 2014, 69:1267-1274.
In all forms of systemic mastocytosis, anti-mediator drugs are used to control symptoms of mast cell degranulation. In advanced forms of systemic mastocytosis, organ damage is common and patients exhibit reduced life expectancy. In these individuals, cytoreductive agents such as cladribine and interferon-alpha have been used off-label, and inhibitors of KIT D816V are under investigation. A significant unmet need exists for these patients.
Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass transmembrane cell surface proteins found predominantly on leukocytes and are characterized by their specificity for sialic acids attached to cell-surface glycoconjugates. The Siglec family contains at least 15 members that are found in mammals (Pillai et al., Annu Rev Immunol., 30:357-392, 2012). These members include sialoadhesion (Siglec-1), CD22 (Siglec-2), CD33 (Siglec-3), myelin associated glycoprotein (Siglec-4), Siglec-5, OBBP1 (Siglec-6), AIRM1 (Siglec-7), SAF-2 (Siglec-8), and CD329 (Siglec-9). Siglec-8 was first discovered as part of efforts to identify novel human eosinophil proteins. In addition to expression by eosinophils, it is also expressed by mast cells and basophils. Siglec-8 recognizes a sulfated glycan, i.e., 6′-sulfo-sialyl Lewis X or 6′-sulfo-sialyl-N-acetyl-S-lactosamine, and contains an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) domain shown to inhibit mast cell function. Anti-Siglec-8 antibodies do not directly affect mast cell viability but antibodies with effector function can induce antibody cell-mediated cytotoxicity (ADCC). However, Natural Killer (NK) cells, an important mediator of ADCC activity, have been reported to be defective in some patients with SM-AHNMD, such as patients with chronic myelomonocytic leukemia (CMML) and patients with myelodysplastic syndrome (MDS). See Marcondes et al. PNAS, 2008, 105:2865-2870 and Kiladjian et al., Leukemia, 2006, 20:463-470. In addition, defective cytotoxicity and reduced receptor expression has been observed in tumor-associated and peripheral blood NK cells of cancer patients. See Pahl et al., Immunobiology, 2015, doi: 10.1016/j.imbio.2015.07.012. Therefore, it is unclear if systemic mastocytosis patients have an intact ADCC function that can be induced to kill mast cells.
All references cited herein, including patent applications, patent publications, and scientific literature, are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference.